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Disruption of dNTPs Homeostasis by Ribonucleotide Reductase Hyperactivation Overcomes AML Differentiation Blockade

ABSTRACT: Disruption of dNTPs Homeostasis by Ribonucleotide Reductase Hyperactivation Overcomes AML Differentiation Blockade

PROVIDER: PRJNA797777 | ENA |

REPOSITORIES: ENA

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Disruption of dNTPs Homeostasis by Ribonucleotide Reductase Hyperactivation Overcomes AML Differentiation Blockade

Project description:Disruption of dNTPs Homeostasis by Ribonucleotide Reductase Hyperactivation Overcomes AML Differentiation Blockade

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Disruption of dNTPs Homeostasis by Ribonucleotide Reductase Hyperactivation Overcomes AML Differentiation Blockade II

Project description:Disruption of dNTPs Homeostasis by Ribonucleotide Reductase Hyperactivation Overcomes AML Differentiation Blockade II

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Disruption of dNTP homeostasis by ribonucleotide reductase hyperactivation overcomes AML differentiation blockade.

Project description:Differentiation blockade is a hallmark of acute myeloid leukemia (AML). A strategy to overcome such a blockade is a promising approach against the disease. The lack of understanding of the underlying mechanisms hampers development of such strategies. Dysregulated ribonucleotide reductase (RNR) is considered a druggable target in proliferative cancers susceptible to deoxynucleoside triphosphate (dNTP) depletion. Herein, we report an unanticipated discovery that hyperactivating RNR enables differentiation and decreases leukemia cell growth. We integrate pharmacogenomics and metabolomics analyses to identify that pharmacologically (eg, nelarabine) or genetically upregulating RNR subunit M2 (RRM2) creates a dNTP pool imbalance and overcomes differentiation arrest. Moreover, R-loop-mediated DNA replication stress signaling is responsible for RRM2 activation by nelarabine treatment. Further aggravating dNTP imbalance by depleting the dNTP hydrolase SAM domain and HD domain-containing protein 1 (SAMHD1) enhances ablation of leukemia stem cells by RRM2 hyperactivation. Mechanistically, excessive activation of extracellular signal-regulated kinase (ERK) signaling downstream of the imbalance contributes to cellular outcomes of RNR hyperactivation. A CRISPR screen identifies a synthetic lethal interaction between loss of DUSP6, an ERK-negative regulator, and nelarabine treatment. These data demonstrate that dNTP homeostasis governs leukemia maintenance, and a combination of DUSP inhibition and nelarabine represents a therapeutic strategy.

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Disruption of dNTPs Homeostasis by Ribonucleotide Reductase Hyperactivation Overcomes AML Differentiation Blockade

Project description:We assessed global gene expression changes in THP1 cells overexpressing inducible RRM2 non-degradable mutant versus empty vector upon doxycycline induction

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Disruption of dNTPs Homeostasis by Ribonucleotide Reductase Hyperactivation Overcomes AML Differentiation Blockade

Project description:We assessed global gene expression changes in 2'-deoxyguanosine (dG)-treated AML cell lines (U937 and KG1A)

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Project description:KSHV is a principal causative agent of primary effusion lymphoma (PEL) which is lacking of effective treatment. Our previous data have showed that HGF/c-MET pathway is highly active within KSHV+ PEL cells and plays important role in tumor cell survival/growth. By using microarray analysis, we have identified the global gene profile controlled by HGF/c-MET pathway within KSHV+ PEL cell-lines and several novel “druggable” candidates closely related to cancer cell survival/growth, including ribonucleotide reductase (RR). We continue to use microarray analysis to identify the gene profile affected within PEL cells exposure to RR inhibitor, 3-AP.

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Gene expression signature baesd screening identifies ribonucleotide reductase as a candidate therapeutic target in Ewing sarcoma

Project description:There is a critical need in cancer therapeutics to identify targeted therapies that will improve outcomes and decrease toxicities compared to conventional, cytotoxic chemotherapy. Ewing sarcoma is a highly aggressive bone and soft tissue cancer that is caused by the EWS-FLI1 fusion protein. Although EWS-FLI1 is specific for cancer cells, and required for tumorigenesis, directly targeting this transcription factor has proven challenging. Consequently, targeting unique dependencies or key downstream mediators of EWS-FLI1 represent important alternative strategies. We used gene expression data derived from a genetically defined model of Ewing sarcoma to interrogate the Connectivity Map and identify a class of drugs, iron chelators, that downregulate a significant number of EWS-FLI1 target genes. We then identified ribonucleotide reductase M2 (RRM2), the iron-dependent subunit of ribonucleotide reductase (RNR), as one mediator of iron chelator toxicity in Ewing sarcoma cells. Inhibition of RNR in Ewing sarcoma cells led to apoptosis and cell death in vitro and attenuated tumor growth in vivo in a xenograft model. Additionally, we discovered that the sensitivity of Ewing sarcoma cells to inhibition or suppression of RNR is mediated, in part, by high levels of SLFN11, a protein that sensitizes cells to DNA damage. This work demonstrates a unique dependency of Ewing sarcoma cells on RNR and supports further exploration of clinically used inhibitors of RNR as a therapeutic approach in treating this cancer.

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DOPA formation on tyrosine Y150 of Ribonucleotide reductase QSK R2e variant from Gardnerella vaginalis.

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2023-09-08 | PXD045227 | Pride

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